Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Preclinical studies in animal models have demonstrated that agonistic engagement of the immune costimulatory molecule 4-1BB/CD137 leads to enhanced activity of cytotoxic T and NK cells, with effective antitumor responses. To assess whether 4-1BB/CD137 engagement improves tumor control in patients, Segal and colleagues evaluated the 4-1BB/CD137 agonist monoclonal antibody utomilumab in a phase I, dose-escalation study in patients with advanced malignancies. Utomilumab was well tolerated at the doses evaluated with no dose-limiting toxicities. Treatment was associated with preliminary evidence of antitumor activity, with durable responses in 2 patients with Merkel cell carcinoma and disease stabilization, as best response, in 13 patients (n = 53). Five of these 13 patients maintained stable disease for &gt;6 months. The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies.Immunotherapy against PD-1 or PD-L1 has shifted the treatment paradigm in lung cancer, despite modest efficacy as monotherapy in PD-L1 negative tumors. B7x and HHLA2 are newly discovered members of the B7-CD28 immune checkpoint family. Cheng and colleagues show that both B7x and HHLA2 are widely expressed in lung cancers. There is limited coexpression of PD-L1 with B7x and HHLA2, although B7x and HHLA2 are commonly found in PD-L1 negative tumors. Functionally, all three checkpoint molecules suppress TCR-mediated proliferation of T cells and cytokine production from T cells. These results suggest that B7x and HHLA2 are potential immune escape mechanisms in these tumors and thus pave the way for designing novel combined or alternative immunotherapeutic strategies.Due to uneven geographical distribution and few trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. Chen and colleagues performed an individual patient data pooled analysis of four randomized trials to comprehensively evaluate the precise role of IC+CCRT versus CCRT alone in locoregionally advanced NPC. The findings indicate the benefits associated with the addition of IC to CCRT, including significant improvements in survival and a reduction in distant failure, with good compliance and tolerable toxicity. IC+CCRT shows promise as an optimal strategy for locoregionally advanced NPC.The importance of HER3 receptor signaling in the development of acquired resistance to drugs targeting EGFR and HER2 is widely recognized. This underscores the need for novel molecular imaging approaches to identify and monitor patients who may benefit from treatment with therapeutic agents that block HER3 activity, potentially overcoming drug resistance. Martins and colleagues have developed a ZHER3:8698-based PET imaging probe that rapidly provides quantitative information about HER3 expression and was able to monitor HER3 upregulation induced by Hsp90 inhibition in breast cancer xenograft models. The results suggest that the clinical application of a HER3-specific PET probe may serve as a valuable tool in augmenting treatment personalization.